Assessment of TLR4 and TLR9 signaling and correlation with human papillomavirus status and histopathologic parameters in oral tongue squamous cell carcinoma

Abstract

Toll-like receptors (TLRs) may promote or inhibit tumor progression. The aim of this study was to assess the expression of TLR4 and TLR9 and their downstream targets in oral tongue squamous cell carcinoma (OTSCC) in correlation with histopathologic parameters and human papillomavirus (HPV) status. OTSCC (fully or superficially invasive and in situ) were studied. Immunohistochemical expression of TLR4, TLR9, nuclear factor-κΒ (NF-κΒ/p65), and interferon-β (IFN-β) was evaluated in tumor and inflammatory cells and in adjacent morphologically normal mucosa. HPV status was also determined. TLR4 showed increased expression levels in tumor and infiltrating inflammatory cells compared with adjacent mucosa, especially in fully invasive cases; a negative correlation between TLR4 levels in inflammatory cells and tumor grade was observed. TLR9 was upregulated in tumor and infiltrating inflammatory cells compared with the adjacent mucosa; its expression in inflammatory cells was higher in well differentiated tumors. NF-κΒ and IFN-β were elevated in cancerous tissues, especially in fully invasive cases, and positively correlated with TLR4 and/or TLR9. HPV positivity (detected in 15.9% of the cases) demonstrated positive correlation with TLR9 and NF-κΒ levels. TLR4 and TLR9 are upregulated in OTSCC and its microenvironment and, by affecting important downstream molecules, such as NF-κB and IFN-β, may play a role in oral cancer development and progression.